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With the government going after fixed drug combinations, it has left disagreement in its wake. Several diabetics and doctors are still to come to terms with the ban.

If there is such a thing as a Richter scale for the Indian pharmaceutical industry, then the Centre’s announcement in March banning a clutch of Fixed Dose Combinations (FDC) did register pretty high on it.

There was a hue and cry from a vibrant industry employing all manner and form of combinations in the manufacture of drugs. There were arguments in favour of the ban and against it. In the din, a group of people — linked by their condition and impacted by this announcement — struggled to come to terms with the ban. With a bunch of diabetes drugs now being docked, patients on FDC oral glycaemic agents, for example, were left wondering whether they had been prescribed “banned drugs”.

“Of course, the rationale behind going after the FDCs is the fact that there are some irrational combinations. And that kind of intervention is now key. Our point, however is that some important combinations that are very useful for diabetics, and that have been in use over about a decade, have been included in the general list,” says Dr. A. Panneerselvam, senior diabetologist based in Chennai.

“With some of the diabetes FDCs, we have managed to achieve excellent blood sugar control in patients who were otherwise taking very heavy doses of insulin,” he goes on to add. A case in point is the dual drug combo of pioglitazone (7.5 mg) and metformin (500 mg). Pioglitazone came under a cloud a couple of years ago, after some reports claimed it caused bladder cancer, but that was cleared subsequently and Pio, as diabetologists call the drug, was declared safe to use.

“ The dosage we give — 7.5 mg of pio — is what is called a mosquito dose. It is pretty tiny, but has a huge positive impact for the patient. In combination with metformin, the drug has been extremely effective for some patients,” Dr. Panneerselvam adds. A case in point is senior citizen Adikesavan. At 82, he has been on treatment for diabetes for nearly three decades now. “In 2007, I was on heavy doses of insulin, and was struggling with blood sugar control. That is when my diabetologist put me on the pioglitazone 7.5 mg + metformin (500 mg) combination, and that seemed like a little miracle for me. Today, I control my diabetes with only medicines, and now, I’m trying to understand why that drug should be banned,” he says.

The trick is that the first molecule is insulin sensitive and attacks the root of the problem, working in very mild doses too. “The key is to use your clinical judgment to determine the right dosage for the patient, and ensure that side effects do not ensue,” explains Dr. Nanditha Arun, director and consultant diabetologist, Dr. A. Ramachandran’s Diabetes Hospitals, Chennai. “We do not use the three-dose combinations that much, but the two-dose FDCs have been helping patients quite a bit. Now they have to go on to take the same drugs, but instead of in a combo, as different drugs, adding to the pill burden,” she adds.

Pill fatigue

The nub of the issue perhaps, is just that — pill fatigue. “For a person diagnosed with diabetes, there are multiple risk factors. Being a metabolic disorder, we often have to start with more than one drug at diagnosis itself — looking at cholesterol, blood pressure, heart disease…And the drugs are for life. So combinations help to a great extent by bringing down the number of drugs that a patient takes,” Dr. Nanditha adds.

That is what Mr. Adikesavan will have to do now. His doctor has rewritten the prescription regimen now, and it has more drugs on it than it used to. “Cost-wise, there is not much of a change, but now I have to take more drugs,” he sighs.

There are indeed irrational combinations even in the treatment of diabetes, points out Dr. Panneerselvam — those that try to add vitamins to oral glycemic agents, and sometimes, statins. “We do not recommend those drugs. The ones that have been banned are those that are rational, and of immense benefit to patients. The Drug Controller General of India should consider withdrawing at least these combinations,” he says.

The moment the drugs were withdrawn from the market, some diabetics started to panic, not so much because the drugs were no longer available, but because they thought the doctor had written out prescriptions for ‘banned drugs.’

Parvati S., a 45-year-old lady who was diagnosed with diabetes scarcely two years ago from Aminjikarai in Chennai, said the moment she heard that the drug was banned, she immediately was anxious about having taken an 'unsafe drug' for the past couple of years. “I actually challenged my doctor and he had to sit me down to explain that the drugs were safe, and that they were working very well for me. That they were good for me, I know. Then why were they banned?”

This confusion is not unique to Mrs. Parvati. Dr. V.Shantaram, senior diabetologist, explains that a number of patients did have similar queries. “The other thing is, the moment you increase the number of drugs, compliance come down. While cost might be a minor issue in this particular case, compliance is what we are bothered about when we increase the number of drugs, or split the combination drugs.”

A question of pharmacokinetics

Playing the devil’s advocate here, Dr. V. Mohan, Dr. Mohan’s Diabetes Specialties Centre, Chennai, says with combination drugs, one tends to lose flexibility. “ For instance, sulphonylurea needs to be given before food and metformin after food. So as a combination, when do you recommend the drug -before or after food?” There are other issues, since FDCs come in different strengths, increasing the dose of one drug means you also unwittingly increase the dose of the other drug in the combo. “That really might not be necessary,” he says, and points out that in an unregulated drug market such as exists in India, and the glut of drugs in different combinations available, it becomes next to impossible to check if the drugs and their various combinations have indeed been cleared for safety and efficacy before prescribing them. “We are not sure if the pharmacokinetics is as predicted with these doses,” he says, however, readily acknowledging that compliance is, for sure, a key issue, one that diabetologists cannot wish away.

Pharmacovigilance is indeed of great significance in a market such as this — it is essential to keep a close watch on the drugs that are being manufactured and what goes into them, in the interests of the public. As the Jan Swasthya Abhiyan, the movement for public health, puts it, “The Central Drug Standards Control Organisation should specify inclusion criteria based on clear scientific evidence for FDCs, and all FDCs that do not fulfill the criteria should be banned.”

It is crucial to get rid of the bad eggs in the basket. But equally important is ensuring that patients do continue to benefit from taking rational combinations that also facilitate compliance.